9-41127170-C-A

Variant names:

• chr9-41127170-C-A
• rs1300152302
• NM_001085476.4:c.1214G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001085476.4(FOXD4L6):​c.1214G>T​(p.Arg405Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXD4L6 NM_001085476.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.76
• Publications: 0 publications found

Genes affected

FOXD4L6 (HGNC:31986): (forkhead box D4 like 6) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in anatomical structure morphogenesis; cell differentiation; and regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

FRG1HP (HGNC:51767): (FSHD region gene 1 family member H, pseudogene)

ENSG00000308937 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.094792336).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085476.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD4L6	NM_001085476.4	MANE Select	c.1214G>T	p.Arg405Leu	missense	Exon 1 of 1	NP_001078945.1	Q3SYB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXD4L6	ENST00000622588.2	TSL:6 MANE Select	c.1214G>T	p.Arg405Leu	missense	Exon 1 of 1	ENSP00000484875.1	Q3SYB3
	FRG1HP	ENST00000617940.2	TSL:6	n.412-67931C>A		intron	N/A
	ENSG00000308937	ENST00000837379.1		n.683+1532C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000669 AC: 1 AN: 149580 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000672

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000498 AC: 3 AN: 60200 AF XY: 0.0000329

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000132 AC: 19 AN: 1443024 Hom.: 0 Cov.: 34 AF XY: 0.0000139 AC XY: 10 AN XY: 717354

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33124

American (AMR) AF: 0.000371 AC: 16 AN: 43128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39338

South Asian (SAS) AF: 0.00 AC: 0 AN: 85600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1099594

Other (OTH) AF: 0.0000168 AC: 1 AN: 59520

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000796227), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000669 AC: 1 AN: 149580 Hom.: 0 Cov.: 26 AF XY: 0.0000137 AC XY: 1 AN XY: 72852

African (AFR) AF: 0.00 AC: 0 AN: 40712

American (AMR) AF: 0.0000672 AC: 1 AN: 14882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 4788

South Asian (SAS) AF: 0.00 AC: 0 AN: 4676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67280

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_noAF	Benign	-0.31
CADD	Benign	2.8
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.095	T
PhyloP100		-2.8
Sift4G	Benign	0.18	T
Vest4		0.10
gMVP		0.013

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1300152302; hg19: chr9-70919081;